The present invention relates to water soluble polycarbonates for medical applications, and more specifically to water soluble polycarbonates for controlled delivery of therapeutic agents such as drugs.
Poly(ethylene glycol) (PEG), which has the structure
is the standard for synthetic water-soluble polymers used for therapeutic delivery. PEG is synthesized by a ring opening polymerization of ethylene oxide. In general, PEG can have a wide range of molecular weights and a narrow polydispersity index (PDI). PEG is soluble in a wide range of organic solvents and water. Furthermore, reactive functionalities can be introduced with ease into PEG macromolecules, making it an excellent candidate for the functionalization of biologically important materials.
Herein, materials possess “stealth properties” if they exhibit low propensity to interact with biological materials (e.g., opsonins) of the physiological environment (e.g., blood stream). When PEG is present in the blood stream, a protective sheath of hydrogen bonded water molecules surrounds the PEG chains. The hydrated PEG chains can exhibit excellent stealth properties. For example, PEG-stabilized drug compositions have been characterized as having reduced enzymatic degradation, decreased uptake by the reticular endothelial system, and reduced renal filtration, which in turn lead to increased blood circulation half-life and bioavailability. Attaching PEG to a therapeutically useful material (e.g., drug) can also significantly decrease the toxicity of the material.
Herein, the term “PEGylated” means comprising a PEG polymer chain. The PEG can be bound covalently and/or non-covalently. PEGylated products have been on the market for approximately 20 years.
A drawback of PEG is its non-biodegradability. The molecular weight necessary for renal clearance is difficult to determine. Generally, PEG that has a number average molecular weight below about 20 kDa can be excreted into urine. PEG that has a number average molecular weight (Mn) above 40-60 kDa is prone to accumulate in the liver. Higher molecular weight PEG can also accumulate at other body sites by mechanisms that remain unknown. PEG accumulation is not a high concern when used short term, but for repeated administration such as with chronic disease treatment, the use of high molecular weight PEG is a concern. PEG having a number average molecular weight (Mn) of about 40 kDa is commonly used for PEGylation of biologically active molecules.
In addition to PEG being non-biodegradable, the side products (e.g. 1,4-dioxane) formed during PEG synthesis and the residual unreacted ethylene oxide monomer are toxic. These byproducts are known carcinogens and are regulated for pharmaceutical grade PEG.
Immunological responses have also been associated with PEG. Although PEG is a stealth polymer, in some formulations PEG induces an immune response when administered intravenously, orally, and/or dermally.
The disadvantages associated with PEG provide motivation to develop alternative polymers for therapeutic delivery of therapeutic agents (e.g., hydrophobic drugs). Although significant research has been performed in this area, there are few synthetic alternatives offering the same stealth properties that can be prepared with the same level of synthetic control. A desirable PEG replacement would biodegrade into non-toxic byproducts. Scheme 1 shows examples of some current biodegradable PEG replacements based on poly(amino acids), where each subscript m is independently a number having an average value greater than 1. Of the three polymers shown, only poly(L-glutamic acid) is approved by the U.S. Food and Drug Administration (FDA).

Other non-biodegradable polymers are also of interest as PEG alternatives (Scheme 2, where each subscript m is independently a number having an average value greater than 1). Many of these polymers are promising as PEG alternatives for applications where only low molecular weight polymers are needed. At high molecular weights, bioaccumulation can become problematic. Poly(N-(2-hydroxypropyl) methacrylamide) and poly(glycerol) have reached clinical trials.

A few biodegradable water soluble polycarbonates have been prepared as alternatives to PEG. These are shown in Scheme 3, where in each case subscript m is independently a number having an average value greater than 1.

The sugar-containing polymers are limited because receptors of the body can bind to sugars. For example, galactose can be used to target liver cells. The polycarbonates containing the short PEG side groups can be used as an alternative to PEG; however, these are synthetically challenging to work with because of ring chain equilibrium. The bulkier the side chain, the more difficult it is to obtain a high degree of polymerization. The remaining polycarbonates are negative-charged, which limits their solubility in organic solvents.
Therefore, a need continues for hydrophilic polymers suitable for delivery of therapeutic agents for medical treatments. The hydrophilic polymers should be biodegradable, non-toxic, and soluble in organic solvents and water. The hydrophilic polymers should not induce an undesirable immune response. The hydrophilic polymers should be accessible in a range of molecular weights having narrow PDIs, and should degrade to non-toxic byproducts.